Paul D. Sponseller

The revised Ghent nosology for the Marfan syndrome

The diagnosis of Marfan syndrome (MFS) relies on defined clinical criteria (Ghent nosology), outlined by international expert opinion to facilitate accurate recognition of this genetic aneurysm syndrome and to improve patient management and counselling. These Ghent criteria, comprising a set of major and minor manifestations in different body systems, have proven to work well since with improving molecular techniques, confirmation of the diagnosis is possible in over 95% of patients. However, concerns with the current nosology are that some of the diagnostic criteria have not been sufficiently validated, are not applicable in children or necessitate expensive and specialised investigations. The recognition of variable clinical expression and the recently extended differential diagnosis further confound accurate diagnostic decision making. Moreover, the diagnosis of MFS—whether or not established correctly—can be stigmatising, hamper career aspirations, restrict life insurance opportunities, and cause psychosocial burden. An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines.

Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis

Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for osteoarthritis due to limited understanding of osteoarthritis pathogenesis. We show that TGF–β1 is activated in the subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) osteoarthritis mouse model. TGF–β1 concentrations also increased in human osteoarthritis subchondral bone. High concentrations of TGF–β1 induced formation of nestin+ mesenchymal stem cell (MSC) clusters leading to aberrant bone formation accompanied by increased angiogenesis. Transgenic expression of active TGF–β1 in osteoblastic cells induced osteoarthritis. Inhibition of TGF–β activity in subchondral bone attenuated degeneration of osteoarthritis articular cartilage. Notably, knockout of the TGF–β type II receptor (TβRII) in nestin+ MSCs reduced development of osteoarthritis in ACLT mice. Thus, high concentrations of active TGF–β1 in the subchondral bone initiated the pathological changes of osteoarthritis, inhibition of which could be a potential therapeutic approach.

Complications of growing-rod treatment for early-onset scoliosis: analysis of one hundred and forty patients.

BACKGROUND Previous reports have indicated high complication rates associated with non-fusion surgery in patients with early-onset scoliosis. This study was performed to evaluate the clinical and radiographic complications associated with growing-rod treatment. METHODS Data from the multicenter Growing Spine Study Group database were evaluated. Inclusion criteria were growing-rod treatment for early-onset scoliosis and a minimum of two years of follow-up. Patients were divided into treatment groups according to rod type (single or dual) and rod location (subcutaneous or submuscular). Complications were categorized as wound, implant, alignment, and general (surgical or medical). Surgical procedures were classified as planned and unplanned. RESULTS Between 1987 and 2005, 140 patients met the inclusion criteria and underwent a total of 897 growing-rod procedures. The mean age at the initial surgery was six years, and the mean duration of follow-up was five years. Eighty-one (58%) of the 140 patients had a minimum of one complication. Nineteen (27%) of the seventy-one patients with a single rod had unplanned procedures because of implant complications, compared with seven (10%) of the sixty-nine patients with dual rods (p ≤ 0.05). Thirteen (26%) of the fifty-one patients with subcutaneous rod placement had wound complications compared with nine of the eighty-eight patients (10%) with submuscular rod placement (p ≤ 0.05). The patients with subcutaneous dual rods had more wound complications, more prominent implants, and more unplanned surgical procedures than did those with submuscular dual rods (p ≤ 0.05). The risk of complications occurring during the treatment period decreased by 13% for each year of increased patient age at the initiation of treatment. The complication risk increased by 24% for each additional surgical procedure performed. CONCLUSIONS Regardless of treatment modality, the management of early-onset scoliosis is prolonged; therefore, complications are frequent and should be expected. Complications can be reduced by delaying initial implantation of the growing rods if possible, using dual rods, and limiting the number of lengthening procedures. Submuscular placement reduces wound and implant-prominence complications and reduces the number of unplanned operations.

Deep wound infections after neuromuscular scoliosis surgery : A multicenter study of risk factors and treatment outcomes

Study Design. A retrospective case–control study evaluating risk factors for infection, causative organisms, and results of treatment in patients with cerebral palsy or myelomeningocele who underwent fusion for scoliosis was performed. Objectives. To identify risk factors for infection, and to characterize the infections in terms of infecting organisms and response to treatment. Summary of Background Data. No previous studies have analyzed risk factors or causative organisms, nor have they indicated results of treatment for infections in this group of patients. Methods. After a 10-year retrospective review of 210 surgically treated patients, deep wound infections developed in 16 patients with myelomeningocele and 9 patients with cerebral palsy. These patients were studied extensively for possible risk factors, along with 50 uninfected patients matched for age, diagnosis, and year of surgery. Statistical testing was performed to identify risk factors. The courses of the infections were characterized in terms of organisms isolated and response to treatment. Treatment was performed in a stepwise fashion and classified in terms of the most successful step: debridement and closure, granulation over rods, or instrumentation removal. Results. Of the 10 risk factors tested, 2 were found to be significant: degree of cognitive impairment and use of allograft. Findings showed that 52% of the infections were polymicrobial. Gram-negative organisms were isolated as commonly as gram-positive organisms. The most common organisms were coagulase-negative Staphylococcus, Enterobacter, Enterococcus, and Escherichia coli.— Debridement and closure were successful in 11 of 25 patients with deep wound infection. Of the 14 patients with infection not resolved by serial debridements and closure, 2 were managed successfully by allowing the wound to granulate over rods, and 7 required rod removal for persistent wound drainage. There were three symptomatic pseudarthroses. Infections resulting from gram-positive organisms were most often managed successfully with debridement and closure (P = 0.012). Conclusions. Patients with cerebral palsy or myelomeningocele who have severe cognitive impairment, and those who received allograft may be at increased risk for infection. Infections are more often polymicrobial andcaused by gram-negative organisms than is typical for elective orthopedic procedures. This suggests an enteric source. Treatment with debridement and closure was not always successful. Patients in whom infection develops are then at increased risk for pseudarthrosis.

Titanium elastic nailing of fractures of the femur in children. Predictors of complications and poor outcome.

Between 1996 and 2003 six institutions in the United States and France contributed a consecutive series of 234 fractures of the femur in 229 children which were treated by titanium elastic nailing. Minor or major complications occurred in 80 fractures. Full information was available concerning 230 fractures, of which the outcome was excellent in 150 (65%), satisfactory in 57 (25%), and poor in 23 (10%). Poor outcomes were due to leg-length discrepancy in five fractures, unacceptable angulation in 17, and failure of fixation in one. There was a statistically significant relationship (p = 0.003) between age and outcome, and the odds ratio for poor outcome was 3.86 for children aged 11 years and older compared with those below this age. The difference between the weight of children with a poor outcome and those with an excellent or satisfactory outcome was statistically significant (54 kg vs 39 kg; p = 0.003). A poor outcome was five times more likely in children who weighed more than 49 kg.

The anatomy of the pelvis in the exstrophy complex

We compared computerized tomography scans of the pelvis of twenty-four patients who had exstrophy of the bladder with scans of age-matched controls in order to analyze the pelvic deformity that accompanies the variably severe manifestations of this condition. The patients who had classic exstrophy of the bladder were found to have a mean of 12 degrees of external rotation of the posterior aspect of the pelvis on each side, retroversion of the acetabula, a mean additional 18 degrees of external rotation and 30 per cent shortening of the pubic rami, and progressive diastasis of the symphysis pubis. The foot-progression angle demonstrated 20 to 30 degrees of external rotation beyond the normal limits seen in early childhood, but this improved with age. The patients who had exstrophy of the cloaca and the bladder not only had all of these pelvic deformities to a greater degree but also had asymmetry of measured parameters between the right and left sides of the pelvis, malformation of the sacro-iliac joints, and occasional dislocation of the hip. An understanding of the pelvic anatomy that accompanies exstrophy is essential when corrective approaches are planned. Such an understanding will improve the rate of success of both closure of the bladder and control of urinary continence postoperatively.

Comparing reliability and validity of pediatric instruments for measuring health and well-being of children with spastic cerebral palsy.

This study sought to examine the reliability and validity of three generic instruments for measuring the health of children with cerebral palsy (CP) and to compare them with a disease-specific measure, the Gross Motor Function Measure (GMFM). The Pediatric Evaluation and Disability Inventory (PEDI), the Pediatric Outcomes Data Collection Instrument (PODCI), and the Child Health Questionnaire (CHQ) were completed by the primary caregivers of 115 young children with spastic CP. The GMFM was administered to the children. The mean age of the sample was 5 years 8 months (range 3:1 to 10:4) and consisted of more males (58%) than females. The PEDI scales demonstrated higher internal consistency than the PODCI and CHQ scales. In comparison with the GMFM, the PODCI transfer and mobility scale (relative validity, 62%) and the PEDI mobility scale (relative validity, 53%) detected the most significant health differences between children with hemiplegia, diplegia, and quadriplegia. The PEDI social function scale detected the largest differences in cognitive function between children with an IQ of less than 70 compared with those with an IQ of 70 or greater. The reliability and validity of these different instruments varied significantly in this patient population.

Loeys-Dietz syndrome: a primer for diagnosis and management.

Loeys–Dietz syndrome is a connective tissue disorder predisposing individuals to aortic and arterial aneurysms. Presenting with a wide spectrum of multisystem involvement, medical management for some individuals is complex. This review of literature and expert opinion aims to provide medical guidelines for care of individuals with Loeys–Dietz syndrome.Genet Med 16 8, 576–587.Genetics in Medicine (2014); 16 8, 576–587. doi:10.1038/gim.2014.11

The thoracolumbar spine in Marfan syndrome.

We analyzed the prevalence, inheritance, progression, and functional implications of spinal deformity in Marfan syndrome using four different groups of patients. We studied 113 patients who had Marfan syndrome, eighty-two of whom were skeletally immature, in order to characterize the alignment and function of the spine. The patients were selected from a clinic that provides total care with no bias toward the presence of orthopaedic conditions. Scoliosis was identified in fifty-two of the eighty-two patients, and the prevalences for the sexes were equal. The thoracic portion of the curve was convex to the right in all but two patients. The mean kyphosis was greater than that in the general population. Five distinct sagittal profiles were identified on the basis of whether the thoracic kyphosis was within, greater than, or less than normal limits and whether the transition between the kyphosis and lordosis occurred at or caudad to the normal level or whether the curves were reversed. Spondylolisthesis was present in five patients (6 per cent), with a mean slip of 30 per cent. Fourteen pedigrees were studied in depth. There was no familial pattern of the scoliosis. A separate group of fifty-six patients with scoliosis, for whom serial follow-up radiographs were available, was studied for progression. Patients who had a curve of more than 30 degrees had mild progression, and those who had a curve of more than 50 degrees had marked progression (mean, 3 +/- 4 degrees per year). Pain and function of the back were studied in thirty patients who were thirty-five to forty-five years old; these patients were found to be more impaired than matched controls. The presence of scoliosis was associated with pain in the region of the curve in these patients.

Fractures of the Femoral Shaft in Children. Incidence, Mechanisms, and Sociodemographic Risk Factors*

BACKGROUND Fractures of the femoral shaft in children are caused by major musculoskeletal trauma and result in high direct and indirect medical costs. To date, the American literature has focused on treatment options and outcomes, but the epidemiology of these injuries has been generalized from Scandinavian studies reported in the 1970s and early 1980s. The goals of the current study were (1) to determine the age, gender, and race-specific rates and mechanisms of fractures of the femoral shaft in children in a large United-States-based population and (2) to identify associations between the rates of these fractures and multiple sociodemographic indicators. Such information is vital for preventive efforts. METHODS The Hospital Discharge Database of the Maryland Health Services Cost Review Commission for the years 1990 through 1996 was used to obtain demographic data on 1485 cases of acute fracture of the femoral shaft in patients who were less than eighteen years old, and data from the United States Bureau of the Census for the state of Maryland for the year 1990 were used to obtain denominator data. Reliable external-cause data were available from the 1995 and 1996 databases for 472 patients. Small-area analysis was performed at the zip-code level to determine associations between numerous sociodemographic indicators and the rate of femoral shaft fracture. RESULTS The annual rate of femoral shaft fracture in children was 19.15 per 100,000. With regard to age, there was a bimodal distribution, with peaks at two and seventeen years. Boys had higher rates of fracture than did girls at all ages, and blacks had higher rates than did whites. The primary mechanisms of fracture were age-dependent and included falls, for children less than six years old; motor vehicle-pedestrian accidents, for those six to nine years old; and motor-vehicle accidents, for teenagers. Firearm-related injuries accounted for 15 percent of the fractures among black adolescents. Adverse socioeconomic conditions were significantly associated with higher rates of fracture. CONCLUSIONS The rates and mechanisms of femoral shaft fractures in children depend on age, gender, and race. For children living in the United States today, the epidemiology of these fractures is different than that described in earlier, Scandinavian reports.